3.2g of Beta Alanine Reduce Rate of Perceived Exertion, Increase Time to Exhaustion and Ventilatory Threshold. Vegetarians, Older People and Diabetics May Benefit Most.

Image 1: If you are into running, ladies, beta alanine is for you ;-)

Those of you who make sure that they are getting their highly educative daily dose of the SuppVersity *rofl* will be aware that today's blogpost is, once again, dealing with beta alanine. Contrary to yesterday's post, which dealt with its pharmacokinetics, we are today going to have another look at what kind of real world performance outcomes the average (female!) physical culturist can expect from taking at least 3.2g of the beta amino acid per day - a dosage that has been shown in previous studies to increase intra-muscular carnosine levels by 27–39% in fast- and slow-twitch muscle fibers, respectively (Baguet. 2009). And though I do not want to spoil things, I can already tell you that the results make it quite clear why beta alanine is not the next creatine.

Somehow ergogenic, yet not really antioxidant

For the study that was conducted at the Applied Physiology Laboratory at the University of North Carolina, study that was conducted by A.E. Smith recruited 24 "recreationally active" women, of which the authors state that they "engag[ed] in 3–7 days per week of aerobic, resistance or recreational activities, but were not highly trained competitive athletes". With a mean age of 21.8 years, a height of 165cm and a body weight of 61.5kg the subjects are thusly representative of the average young woman who goes to the gym to either get or keep in shape. I am specifically emphasizing this, because - at least in the early days - beta alanine was heavily marketed as "the creatine for women" who fear the water retention people still claim was an inevitable side effect of creatine supplementation.

Image 2: If you retain water, this is not due to creatine monohydrate. Either you are taking to much (creatine loading is a thing of the past) or you have bought a product with shitloads of carbs in it - in that case, chances are its not only water you are gaining ;-)

Does creatine supplementation inevitably lead to water retention and weight gain? Just because this myth is still perpetuated, especially among female figure competitors, I thought it may be worth addressing this again: Pure creatine monohydrate without the sugar and the other bullshit you will find in many creatine supplements does not necessarily lead to increases in either total body or water weight. A study by Rawson et al. showed only recently that the consumption of 0.03g/kg creatine for six weeks did not result in statistically significant changes in body weight or water in men or women, despite significantly increased plasma creatine concentration and enhanced resistance to fatigue during repeated bouts of high-intensity contractions (Rawson. 2011).

The women were advised to simply stick to their usual routine and to refrain from taking any supplements and medications except from their 2x800mg beta alanine tablets. The latter were to be taken 3x a day... so according to Cocker, they should have consumed 2x0.8g x3/day = 4.8g/day and not, as the scientists state "3.2 g daily". Now, according to Smith et al. this was the "required dosage" all participants met. I can however not say, whether this means that the third dose was optional... and this is not the only oddity in this study, where it is well worth to look beyond the assessments and conclusions of the authors.

At the beginning and the end of the 28-day supplementation period, the women had to perform a graded oxygen consumption test (VO2max) to evaluate VO2max, time to exhaustion, ventilatory threshold and establish peak velocity (PV), as well as a "non-damaging treadmill run (oxidative stress run) for 40 min at 70% PV [peak velocity]". Before, immediately after and in the 2-6h post running window total antioxidant capacity (TAC), superoxide dismutase (SOD), 8-isoprostane (8ISO) and reduced glutathione (GSH) were measured. In addition to that, heart rate and ratings of perceived exertion were recorded during the 40 min run. The two main metrics of the study were thusly the potential anti-oxidant effects (TAC, SOD, 8ISO, GSH) and the anticipated immediate ergogenic effects (VO2Max, time to exhaustion, heart rate and perceived exertion) of beta alanine supplementation.

Figure 1: Effect of 28 days of beta alanine supplementation on maximal oxygen consumption (VO2max), time to exhaustion during a graded exercise test (VO2TTE) and ventilatory threshold (VT) and qualitative practical significance (data and caption adapted from Smith. 2011)

If you now have a look at the my graphical rehash of the scientists own evaluation of the effect beta alanine supplementation had on VO2Max, the time to exhaustion (VO2TTE) and the ventilatory threshold (VT), you will have to concede that mean improvements of 0.28%, 6.6% and 3.7%, respectively, as well as the large discrepancies among the subjects (from beneficial over negligible to harmful) do not actually speak for beta alanine.

Figure 2: Effect of beta alanine supplementation on oxidative stress markers measured as total
antioxidant capacity (TAC) and glutathione (GSH) and the qualitative practical significance
for women (data and caption adapted from Smith. 2011)

Things get even more confusing when we take a look at the antioxidant effects of beta alanine. Not only were the levels of superoxide dismutase (SOD) and 8-isoprostane (8ISO) not different between groups, and the effect of beta alanine on the total antioxidant capacity (TOC) of the subjects negligible, the scientists' summary of the effects does even suggest that, after an initial amelioration of the negative effect of treadmill running on GSH, there was some sort of a "likely harmful" rebound 6h after the 40 min exercise bout. Before you do now flush your beta alanine stores down the toilette, I suggest you first take a look at the actual (absolute) effects beta alanine supplementation had on the exercise induced changes in GSH levels:

Figure 3: Absolute GSH levels (in µM) immediately before (pre), post, 2h and 4h after treadmill running in the placebo and beta alanine supplemented women before (pre) and after (post) the 28-day supplementation period (compiled based on data from Smith. 2011)

As you can see in figure 3, there was an (unexplained) increase in GSH in the course of the 28-day supplementation period in both groups. With 2%, the latter was statistically non-significantly greater in the beta alanine group, and the "likely harmful" effect of beta alanine supplementation 6h after the end of the treadmill-run is simply the result of a smaller increase in GSH, when you compare the pre- to post-supplementation levels at the 6h mark - and I guess, you would agree that a +27% increase in GSH is not exactly something that deserves to be called "likely harmful", wouldn't you?

All-clear: Beta alanine is not ergolytic ;-)

Now that we have gotten that straight, let's get to the last (and most) significant benefit the women in the beta alanine group had from taking the supplement: a statistically significant reduction in the rate of perceived exertion during treadmill running (cf. figure 4).

Figure 4: Rates of perceived exertion during 40 min treadmill running before (pre) and after (post) 28 days of supplementation with beta alanine or placebo; small graph: relative difference post supplementation in women receiving BA vs. placebo (data calculated based on Smith. 2011)

It goes without saying that being 18% less fatigued is something that could well be worth spending the roughly 7$ for a 28-day supply on (calculation based on a dose of 3.2g per day taken over 28 days and assuming you buy your beta alanine in bulk at one of the major suppliers). This, by the way, could be particularly true if you belong to one of the following groups, who have been found to have low intra-muscular carnosine levels, to begin with:

Image 3: Older people are only one of the three groups who are "at risk" of low carnosine levels and are thusly most likely to benefit from beta alanine supplementation.

1. vegetarians - a 2011 study by Evaraert et al. found that "Vegetarians have a lower carnosine content of 26% in gastrocnemius compared to omnivores" (Everaert. 2011); and according to another recent study, the soleus carnosine content of vegetarians was "non-significantly" reduced by -9% after 5 weeks of sprint training, while the same protocol elicited increases of +11% in omnivores (Baguet. 2011)
2. older people - Evaraert et al. found a linear decline (ca. -10% in 20 years) in carnosine levels with age (correlation r=-0.26; Everaert. 2011); and Stout et al. report a highly significant +29% increase in physical working capacity at the fatigue threshold in twenty-six men (n = 9) and women (n = 17) (age ± SD = 72.8 ± 11.1 yrs) who  had been supplementing with 800 mg three times per day for 90 days (Stout. 2008)
3. type-2 diabetics - according to Gualano et al. type-2 diabetics have "significantly lower carnosine content (−45%) in gastrocnemius muscle", a relative deficiency of which the scientists argue that it "may be partially associated with defective mechanisms against oxidative, glycative and carbonyl stress in muscle." (Gualano. 2011)

After all, it does yet not really matter whether you are a type-2 diabetic, a vegetarian or simply getting older, compared to many (if not most) of the other overpriced ergogenics that are advertised all over the web, beta alanine is certainly not only one of the cheapest, but also one of the most promising candidates for the 3rd place on your list of staples, where (whey) protein and creatine should nevertheless still occupy position 1 and 2, respectively. And the fact that it did not prove to be a potent antioxidant in this study need not really be a disadvantage, after all, we still do not know whether the exercise-induced oxidative "damage" is not what actually triggers the highly desirable adaptive responses (cf. previous posts on "hormesis"), we are all looking for, when we are hitting the gym.

Alanyl-Glutamine or Alanine + Glutamine? Dipeptide or Free Form Aminos? What Offer Maximal Muscle Protection?

"Wouldn't have happened if she'd used alanyl-glutamine instead of regular that cheap alanine + glutamine combo!" - True or False? Recent study says: False!

If you combine your liver's favorite gluconeogenic amino acids, i.e. alanine and glutamine, into a single peptide the result is called alanyl-glutamine and marketed as the ueber-potent alternative to regular l-glutamine supplements. It goes without saying that a comparison like this is about as stupid as comparing french fries with mayo to regular french fries and saying that the former are worse because they contain more fat, or whatever. Even if we didn't care about the physiological significance of the effects of alanyl-glutamine, we would obviously have to compare the purported cryogenic effects of this "innovative" dipeptide to those of a simple combination of free form amino acids to deserve the bragging rights for having created an advanced form of glutamine.

Alanine + glutamine vs. alanyl-glutamine - fight!

By now you are probably asking yourselves why I am bothering you with things like this. Right? Well, the reason is that Éder Ricardo Petry and his colleagues from the University of Sao Paulo must recently have been pondering the same question. To answer it, they conducted an experiment that would allow them to verify if the oral supplementation with l-glutamine and l-alanine as dipeptide has more pronounced muscle protective effects than a simple mixture of l-glutamine and l-alanine (GLN+ALA, both in their free forms) in a group of Wistar rats that are subjected to intense aerobic training (treadmill).

I know what you are thinking now: "Not another rodent study...", but think about it: How many people are willing to pay $50 and more on supplements without any in vivo evidence of their efficacy let alone long-term safety? Against that background Petry's rodent is a major advancement - isn't it?

True or False: You can (ab-)use glutamine to replenish your glycogen stores!? True! It sounds strange, but according to a study from the late 20th century glutamine is a pretty effective glycogen replenisher, even in the absence of your bodies favorite nitrous glucose precursor alanine | learn more

Don't get me wrong, there are a few alanyl-glutamine studies in humans, but there is not a single one that would compare the dipeptide to a reasonable placebo in an exercise scenario. I mean, who tells me that the basketball players in the 2012 study by Hoffman et al. wouldn't have experience the same beneficial effects on basketball skill performance and visual reaction time if their rehydration solution had contained alanine and glutamine or even glutamine alone? Yes, I know... the increased absorption: Well, let's just look at a fair comparison, i.e. the study at hand, and see what happens when the dreams of supplement formulators and reality meet ;-)

Ok, back to the facts - the exercise & supplementation protocol

The male Wistar rats, the researchers used in their experiment were exercised 5x per week - at increasing intensities: Starting with 30 and 45 min of treadmill running (incline 3°) at 20 and 22.5 m/min in the first three weeks, the speed and duration of their treadmill runs increased to 60 min at a speed of 25 m/min in week four and remained like that for the rest of the 8-week study period.

The supplements were administered via oral gavage in the course of the last 3 weeks, only. The daily doses for the animals in the dipeptide (DIP) and free form amino acid groups (GLN+ALA) were...

• 1.5g/kg alanyl-glutamine in the DIP group,
• 0.67g/kg l-alanine + 1.0g/kg l-glutamine in the GLN+ALA group, and
• plain water in the control group

The amount of of alanyl-glutamine the scientists used was calculated in such a way that the total amount of l-glutamine was the same as that of l-glutamine administered in its free form.

Changes? YES! Dipeptide benefits? Not really...

The gavage was provided 1 h after the end of each session of exercise, after which the animals had with free access to water and chow. To make sure that the results of the examinations on the last day of exercise would not reflect the acute effects of a single dose of the supplements, the animals were killed 10 h after the last exercise session.

Figure 1: Plasma glutamine, glutamate, ammonium, malondialdehyde, myoglobin, and creatine kinase activity in Wistar rats supplemented with alanyl-glutamine (DIP) or regular glutamine + alanine; data expressed rel. to control (Petry. 2013)

The virtually identical increases in l-glutamine and l-glutamate, you see in Figure 1 should thus represent the baseline and not the 'immediately post supplementation level' of these amino acids. For the exercise-induced accumulation of ammonium, malondialdehyde (MDA; indicates lower lipid oxidation), myoglobin and creatine kinase (both indicate lower muscle damage) the timing is not that important, anyway. What is important, however, is the fact that there were no physiologically relevant advantages for the "super glutamine".

DHEA & estrogen are alternative muscle protectors. Despite the fact that estrogen has repeatedly been shown to have muscle protective-effects, I would not suggest you steel your granny's HRT medication. DHEA on the other hand, may be something to consider - specifically if you are about to overreach, like the male subjects in a 2012 study by Liao et al. (learn more)

If we take a closer look at the p-values and the statistical significance of these changes, it turns out that, the minor increase in glutamate aside, all of the difference to the placebo group were statistically significant. The DIP vs. GLN+ALA differences, on the other hand, were marginal and reached statistical significance only in the case of the marker of myoglobin. Where the dipeptide has a physiologically probably irrelevant edge of 9% over the GLN + ALA combination.

Figure 2: Glutathione (GSH) and glutathione disulfide (GSSG = used glutathione) levels in soleus and gastrocnemius skeletal muscles of the rodents; data expressed relaitve to control (Petry. 2013)

For the muscular GSH levels, it does not look much different. In this case, there is however not even a statistical difference between alanyl-glutamine and the simple l-alanine + l-glutamine mix - neither for the universal anti-oxidant glutathione (GSH), nor for its "used form" glutathione disulfide (GSSG).

Does that mean that alanyl-glutamine is another supplemental rip-off?I would say that it's too early to use such harsh words. There was after all one statistically, and maybe even physiologically relevant difference between the two groups I didn't mention, yet: The dipeptide group presented with a different heat-shock protein response: They had higher HSP-70 and lower HSF-1 levels in the soleus and lower HSP-70 and lower HSF-1 levels in the gastrocnemius.

"Will training your biceps, heal your heart & protect your brain!?" - a study on the effects of exercise induced HSP increases suggests so | more

In view of the fact that the subsequent "deficit in HSP70 expression" is supposed to "impair recovery from these injuries" Petry et al. are probably right to point out that

"one cannot discard the possibility that part of the beneficial effects of high-intensity exercise training may be due to the enhancement of HSP70 expression which is exacerbated by glutamine supplementation."

In view of the fact that the total amount of proteins from the HSP70 and HSF1 family was increased in both groups, and the differences appear random, it is impossible to tell, whether the slight differences in HSP expression actually matter and whether this is an advantage for alanyl-glutamine or rather for the cheap free form amino acids.

Before future studies provide additional data based on which we can decide whether these differences are relevant and why they differ between slow- (soleus) and fast-twitch (gastrocnemius) skeletal muscle fibers, I'd say that the study at hand would suggest that alanine and glutamine have muscle protective effects irrespective of whether they are bound or not, when you ingest them.

References:

• Cruzat VF, Rogero MM, Tirapegui J. Effects of supplementation with free glutamine and the dipeptide alanyl-glutamine on parameters of muscle damage and inflammation in rats submitted to prolonged exercise. Cell Biochem Funct. 2010 Jan;28(1):24-30. 
• Cruzat VF, Tirapegui J. Effects of oral supplementation with glutamine and alanyl-glutamine on glutamine, glutamate, and glutathione status in trained rats and subjected to long-duration exercise. Nutrition. 2009 Apr;25(4):428-35.
• Hoffman JR, Williams DR, Emerson NS, Hoffman MW, Wells AJ, McVeigh DM, McCormack WP, Mangine GT, Gonzalez AM, Fragala MS. L-alanyl-L-glutamine ingestion maintains performance during a competitive basketball game. J Int Soc Sports Nutr. 2012 Mar 7;9(1):4.
• Petry ER, Cruzat VF, Heck TG, et al. Alanyl-glutamine and glutamine plus alanine supplements improve skeletal redox status in trained rats: Involvement of heat shock protein pathways. Life Sciences. 20 November 2013 [ahead of print]
• Rogero MM, Tirapegui J, Pedrosa RG, Castro IA, Pires IS. Effect of alanyl-glutamine supplementation on plasma and tissue glutamine concentrations in rats submitted to exhaustive exercise. Nutrition. 2006 May;22(5):564-71.

Inflammation Is a True Fat Burner: BSO-Induced Glutathione Depletion Wards off Fat Gains on Hypercaloric Diet

Image 1: This little bugger obviously has too little inflammation going on ;-)

Are you "on fire"? Inflammation has been implicated as the root cause of almost all modern disease: obesity, diabetes, heart disease, cancer, you name it. Soothing the flames via natural and supplemental anti-oxidants has thusly been proposed and marketed as a solution for many of the aforementioned health problems.

Yet, despite tons of vitamins, anti-oxidants and all the other "healthy" stuff we are taking and consuming on a daily basis, the number of morbidly obese people, diabetics and heart attack patients appears to be ever-increasing... how can that be?

A possible answer to that question comes from scientists from the Saha Cardiovascular Research Center at the University of Kentucky College of Medicine in Lexington, Kentucky, US (Findeisen. 2011) - we simply got everything wrong! The observation that insulin resistance and beta-cell dysfunction usually occur in the presence of large amounts so-called reactive oxygen specimen (ROS) lead scientists to propose that there was a causative relationship between these two events, of which the data only shows that they are corollary.

Image 2: Whenever there is a fire, the firefighters are not far away, but does this correlation indicate that all firefighters are firebugs? (img texarkanagazette.com)

Despite the fact that the distinction between correlation and causation should be obvious, correlations have a long history of being mistaken as causative factors in the history of science. The corollary elevation of total cholesterol in heart disease patients, for example, is the reason that millions of well-educated people world-wide still believe that cholesterol would cause heart disease - an erroneous conclusion for which my friend, Carl Lenore, has coined a very fitting analogy (actually the analogy spans all those "corollary causation"): When there is a fire in down-town New York, it won't take long until the place is packed with firefighters, nevertheless, no sane observer would get the idea that the corollary appearance of firefighters on the scene would be the reason for the fire.

Here, at the SuppVersity, you have already learned that a group of researchers from Germany has invested a lot of work into research on the beneficial effects of inflammation (Ristow. 2010). Now, with the data from Hannes M. Findeisen (who unquestionably is a German or has German ancestors, as well ;-) et al., evidence begins to accumulate that the role of reactive oxygen specimen in glucose homeostasis could in fact be a beneficial and not a detrimental one. After all, Findeisen and his colleagues were able to show that the pharmacological depletion of glutathion, our natural broadband fire-extinguisher, made mice resistant to diet-induced obesity, increased energy expenditure and enhanced insulin sensitivity.

If you have listened to all the installments of the Amino Acids for Super Humans Series on Carl Lenore's Super Human Radio, you will already have heard me mention that a methionine/cysteine-free diet has been shown years ago to have profound fat-burning, or I should say, weight-reducing effects on mice - no wonder, with methionine and cysteine being essential substrates for mammalian gluthation production, a lack of these dietary sulfur-amino acids induced a similar glutathion depletion as the addition of 30mmol/l BSO to the drinking water of the mice in the Findeisen study (for more on the glutathion depleting effects of BSO, cf. Skapek. 1998; Mira. 2002; Cattan. 2008)

Even before the works of Ristow et al. and now Findeisen et al., it has been well-established that reactive oxygen specimen, the purported villains of the 21st century, enhance cellular signaling (Veal. 2007). About a year ago, Chang and Chang  reported that H2O2, in particular, is a potent activator of protein signaling pathways, including insulin signaling and can even mimic insulin's effects by the inhibition of oxidation-sensitive protein tyrosinases (Chang. 2010). With glutathion being the primary H2O2 scavenger in mammalian tissue, it is thus not surprising that the BSO treated and thusly glutathion depleted mice in the Findeisen study displayed a more favorable response to a glucose tolerance test after 6 weeks of treatment with BSO and a 45%(high)-fat diet (cf. figure 1).

Figure 1: Glucose levels in mg/dl after oral glucose tolerance test in mice after 6 weeks on a high-fat diet (47% fat) with or without 30mmol/L BSO in their drinking water (data adapted from Findeisen. 2011)

These results are surprising, also because the daily food and water intake of the mice was identical. The latter cannot be said of their calorie-expenditure, daily activity level (cf. figure 2) and the activity of the "fat burning" uncoupling protein UCP2 (+100%), the elevation of which increases thermogenesis and energy expenditure.

Figure 2: Relative changes in energy expenditure and daily activity due to BSO induced glutathion depletion in mice on a high fat diet compared to non-treated control (data calculated based on Findeisen. 2011)

Now, most importantly for you, as a physical culturist, may be that glutathione depleted mice did not simply fail to thrive or shrivel away - they were, as Findeisen points out...

completely protected from diet-induced obesity, despite similar food intake and water consumption. Analysis of body composition in mice fed a HFD diet confirmed significantly decreased fat mass in BSO-treated mice without significant differences in lean body mass, indicating that the difference in body weight was due to reduced fat mass in BSO-treated mice.

If you don't believe the words, I suggest you take a look at the data in figure 3 - while the control mice had a body fat percentage of whopping 32% the mice on BSO with their ~16% body fat were well within the normal range for lab-mice.

Figure 3: Fat and lean mass (in g) of mice from the control group and the glutathion-depleted group after 6 weeks on a hypercaloric high fat diet (data adapted from Findeisen. 2011)

Even the researchers appeared to be surprised by the profound effects glutathion depletion had on the rodent's ability to accumulate body fat. As far as the underlying reasons are concerned, they speculate that it was ...

[...] possible  that  the  observed  increase in the expression of UCP-2 and UCP-3 in BSO-treated mice induced  mitochondrial  uncoupling [...] Alternatively, the enhanced energy expenditure in BSO-treated mice  might  be  the  result  of  increased  locomotor  activity.  In skeletal muscle, ROS are necessary for optimal contractile function, force production, and exercise-induced adaptations. Furthermore, particularly H2O2 is increasingly recognized as
a potent neuromodulator. It is therefore conceivable, that glutathione depletion may lead to activity-stimulating changes in the redox environment of muscle or brain.

Now, it is however questionable in how far any of these three phenomena would occur in human beings, as well. While the lack of large amounts of UCP-sensitive brown adipose tissue would decrease the UCP induced thermogenic response to glutathione depletion, locomotor activity is something that appears to be completely blocked in the modern couch potato, anyways. It would thus warrant further research (and studies into the general safety of this approach) before it would appear warranted that you take a spoon of BSO with every meal to counter the negative effects of your last binge ;-)

Whey Beyond Brawn: 10+ Things You Probably Didn't Know Whey & Peptides That Form During its Digestion Can Do: From A as in Vitamin A Uptake to Z as in CanZer Protection

If you've got brawn and brain you will realize that whey is much more than a potent muscle builder.

As a SuppVersity reader you are well familiar with the pluripotent benefits whey protein has to offer to the average and extra-ordinary gymrat. You will also be aware that it can promote weight loss and help you maintain lean muscle mass, when you're dieting.

If you've read almost all ~2,000 SuppVersity articles, you will even know about the GLUT4 and thus glucose uptake promoting effects isoleucine containing dipeptides in whey protein hyrolysates, but I guess that some of the other benefits whey protein owes to its complex mixture of proteins and peptides are going to be news for you.

Learn more about the effects of your diet on your body composition at the SuppVersity

Only Whey, Not Soy Works for Wheytloss

Minimal Carb Reduction, Max. Results?

Dairy Protein Satiety Shoot-Out: Casein vs. Whey

How Much Carbs Before Fat is Unhealthy?

5 Tips to Improve & Maintain Insulin Sensitivity

Carbohydrate Shortage in Paleo Land

In their latest paper in the Austin Journal of Nutrition and Food Science Rie Tsutsumi and Yasuo M. Tsutsumi provide a concise overview of the biological effects of a range of peptides and proteins in whey protein. The latter include...

• 

  Amino acid composition of whey, casein and breast milk - whey excells in terms of pro-anabolic BCAAs (McDonough. 1974)

  whey is the richest natural source of BCAA -- I don't have to tell you that, but I thought maybe there is someone who has never heard of it before ;-)
• whey protein has the highest biological value (indicative of the most balanced EAA profile) of all dairy proteins (the  biological  value  is  the  ratio  of  the amount of nitrogen that is consumed to the amount of nitrogen that is absorbed, and this value is 74 for soy protein, 71 for casein, and 104 for whey protein)
• whey protein has the highest protein efficacy ratio, i.e. the body weight increase associated with an intake of 1 g protein is 3.0 (vs. 2.0 for soy protein and 2.5 for casein protein)

Whey proteins are however far more than building blocks / muscle builders, the  proteins  in  whey  have a variety of roles and immune-related functions:

• b-lactoglobulin binds retinol (vitamin A) and promotes uptake of retinol via gut; by a similar mechanism it may also facilitate the uptake of long-chain fatty acids
• a-lactoalbumin kills tumour cells (in vitro) and exerts anti-bacterial effects in the upper respiratory systems; it has also been shown to have protective effects on gastric mucosa.

• 

  Table 1: Content of minor bioactive proteins in whey concentrates (levels are probably lower in iso- and hydrolysates | values from Smithers. 2008) and the lactalbumin fractions. Since the major proteins in whey (not listed here) can form bonds with albumin (Havea. 2001), whey is another case, where an increase in processing may lead to a decrease in beneficial biological activity.

  lactoferrin regulates the absorption of iron via gut; it will inhibit the growth of various bacteria and regulates immunological response of immunocomponent cells
• serum albumin binds and carries fatty acids and bile pigment
• immuno-globulin G involves with bactericidal (anti-bacterial) effects with complements and prevents bacteria from adhering to tissues; neutralizes toxins and viruses
• immuno-globulin A inhibits growth of various bacteria by condensing them; prevents bacteria from adhering to the surface of mucosa; neutralizes toxins produced by viruses and bacteria.
• immuno-globulin M has the same effects as IgG, but its bioactivity is stronger
• lactoperoxidase catalyzes the reaction of producing cyanogen ion with strong bactericidal power from cyanic ion and hydrogen peroxide in the body
• lysozyme kills bacteria by destroying cell walls

As the Japanese researchers point out, the mechanisms relating to the whey functions are varied. The antioxidant and detoxifying activity of whey is most likely linked to its contribution to GSH synthesis.

"Cysteine, which contains an antioxidant thiol group, combines with glycine and glutamate to form GSH. GSH is the major endogenous antioxidant produced by cells, providing production for RNA, DNA, and proteins via its redox cycling from the reduced form, GSH, to the oxidized form, GSSH. Though direct conjugation, GSH detoxifies a host of endogenous and exogenous toxins including toxic metals, petroleum distillates, lipid peroxides, bilirubin, and prostaglandins." (Tsutsumi. 2014)

The antioxidant and antimicrobial effects of lactoferrin have already been mentioned above. In addition, lactoferrin demonstrates an ability to stimulate immune responses involving natural killer cells, neutrophils, and macrophage cytotoxicity. Furthermore, a mouse study concluded that lactoferrin acts as an anti-inflammatory by regulating the levels of tumor necrosis factor and interleukin-6.

"Owing to its ability to chelate iron, organisms requiring iron for replication appear to be particularly vulnerable to the effects of lactoferrin. The protein beta-lactoglobulin contains anti-hypertensive peptides, which lower blood pressure as significantly as angiotensin converting enzyme (ACE) inhibitors. Cholesterol-lowering effects have also been noted as a result of changes in micellar cholesterol solubility in the intestine." (Tsutsumi. 2014)

Moreover, the  formation of peptides through the hydrolysis of whey proteins in your tummy is a rather novel, but very interesting effect that may well contribute to the beneficial health efects of whey proteins. In fact, whey peptide is one of the major peptides that inhibit ACE (FitzGerald. 2004), which induces blood-pressure regulating effects.

It is very likely that peptides are also responsible for many of the metabolic benefits

Pal et al. demonstrated a decrease in fasting plasma concentrations of triacylglycerols after long-term whey protein intake (12 weeks) in overweight and obese individuals (Pal. 2010a,b,c). And while the mechanisms behind the effects of whey protein on triacylglycerols are not understood, Mortensen et al. proposed that a meal containing whey might have resulted in reduced production of chylomicrons and accelerated chylomicron clearance resulting from the stimulation of lipoprotein lipase by whey.

Figure 2: Changes in insulin and HOMA-IR (insulin resistance) i response to 12 weeks on 27g of whey vs. casein (vs. control) in overweight / obese subjects (Pal. 2010b)

This would yet not explain the significant improvements in glucose management evidenced by reduced insulin and HOMA-IR values in the whey group of Pal et al.'s 12-week intervention with 27g of whey (vs. glucose vs. casein; cf. Figure 2).

Pal et al. are obviously not the only ones, who observed significant beneficial effects on glucose management in response to the ingestion of whey protein supplements. As Tsutsumi & Tsutsumi point out "[t]he majority of these studies reported that whey protein intake decreases blood glucose and insulin levels" (Tsutsumi. 2014)

Whey a source of bioactive anti-diabetic, pro-satiety peptides?

The latter is interesting, because we know that in type II diabetics, whey protein will increase not decrease the insulin response. I that, the acute effects of whey protein on postprandial blood glucose are comparable to sulfonylureas and other insulin secretagogues used for the pharmaceutical management of hyperglycemia in type 2 diabetes. A benefit that is probably related to bioactive peptides and amino acids that are generated during gastrointestinal digestion and enhance the release of several hormones (including insulin) which are able to reduce the food intake and increased satiety (e.g. cholecystokinin, peptide YY, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1)). How exactly this works is still being researched, but both, ...

• 

  Figure 3: Effects of 48 g casein (full circles) or whey (open squres) on GLP-1 (Hall. 2003)

  the production of bioactive peptides that serve as endogenous inhibitors of dipeptidyl peptidase 4 in the proximal gut, preventing the degradation of the insulinotropic incretins GLP-1 and GIP, as well as ...
• a mechanism that involves BCAAs, specifically leucine, which activates the mTOR signaling pathway and protein synthesis leading to elevated hormone expression and secretion and increased thermogenesis

...have been brought forward and supported by research. In the end, it does not really matter how whey does it. The resulting increases in satiety, thermogenesis, and reduction of blood glucose, which is comparable to pharmaceutical treatment, support the use of whey protein in the management of type 2 diabetes and obesity, anyway.

I won't bore you with the muscle building effects of whey: You just have to click here to see previous articles on whey protein, if you actually feel you need to know more about the muscle building prowess of whey protein.

If whey protein helps prevent or even cure diabesity it will also help to prevent a hell lot of the side effects of being an overweight type II diabetic. And still, researchers believe that there may be a more direct link than diabesity prevention to the following health benefits of whey protein that are listed in Tsutsumi & Tsutsumi's latest review (the following bulletpoints are in large parts direct quotes from Tsutsumi. 2014):

• cancer  -- A number of animal studies have examined the anti-cancer potential of whey, believed to be primarily associated with the antioxidizing, detoxifying, and immune-enhancing effects of GSH and lactoferrin.
  
  A few clinical trials have been undertaken, proposing that high levels of GSH in tumor cells confer resistance to chemotherapeutic agents. One of these studies showed that 20 patients with stage IV malignancies were treated daily with 40 g whey in combination with supplements such as ascorbic acid and a multi-vitamin/mineral formulation (See. 2002). The 16 survivors demonstrated increased levels of natural killer cell function, GSH, hemoglobin, and hematocrit 6 months later. An aggressive combination of immunoactive nutraceuticals was effective in significantly increasing natural killer function, other immune parameters, and plasma hemoglobin in patients with late stage cancers.
• hepatitis B & C -- The results of trials for the hepatitis B virus have been positive,  particularly  those  from  an  open  study  that  included  8  patients administered 12 g non-heated whey/day. The patients demonstrated improved liver function markers, decreased serum lipid peroxidase levels, and increased  interleukin-2  and  natural  killer  cell  activity (Watanabe. 1999)
  
  Regarding hepatitis C, several trials have proved inconclusive, although an initial in vitro study found that bovine lactoferrin prevented the hepatitis C virus in a human hepatocyte line (Ikeda. 1998)

• 

  Figure 4: Next to reductions in blood pressure, whey induced reductions in blood lipids are a likely mechanism behind the reduced CVD risk with whey (illustration from Pal. 2013)

  cardiovascular disease -- According to the results of a number of studies, intake of milk and milk products can lower blood pressure and reduce the risk of hypertension (Marshall. 2004). Kawase et al. performed an 8-week trial in which 20 healthy men were given a combination of fermented milk and whey protein concentrate and examined the effect on serum lipids and blood pressure (Kawase. 2000). After the 8 weeks, the fermented milk group demonstrated comparatively higher high-density lipoproteins, lower triglycerides, and lower systolic blood pressure. 
• hypertension --Various investigators have hypothesized that certain bioactive peptides formed through the hydrolysis of food proteins have the ability to inhibit ACE, and this subject has been comprehensively reviewed in a number of studies. In general, it has been claimed that a diet rich in foods containing anti-hypertensive peptides is effective for the prevention and treatment of hypertension. ACE-inhibitory peptides may be obtained from precursor food proteins via enzymatic hydrolysis, the use of viable or lysed microorganisms, or specific proteases.
  
  However, studies relating to whey peptides with ACE inhibitory activities are more limited; this may be due to the rigid structure of beta-lactoglobulin, which makes it particularly resistant to digestive enzymes. 
• osteoporosis -- Milk basic protein (MBP) is a component of whey that demonstrates the ability to not only suppress bone resorption but also stimulate proliferation and differentiation of osteoblastic cells (Marshall. 2004).
  
  The role of calcium intake in determining bone mineral mass is well recognized to be the most critical nutritional factor to achieve optimal peak bone mass; milk protein is also important for preventing osteoporosis. A number of clinical trials support milk protein’s positive effects in both men and women, the latter ranging in age from young to postmenopausal. Daily doses of 40 mg MBP (equivalent to 400–800 mL milk) appear to be sufficient to significantly increase bone mineral density and reduce bone resorption.

• 

  Figure 5: Mean (±SD) reaction time in the high stress–vulnerable (▪) and low stress–vulnerable (□) groups after consumption of a diet containing protein as sodium casein (control diet) and a diet containing α-lactalbumin–enriched whey protein (α-lactalbumin diet | Markus. 2002)

  stress adaptation -- Whey enriched with the protein alpha-lactalbumin has been shown to improve cognitive performance and mood in stress vulnerable subjects (Markus. 2002). Alpha-lactalbumin is particularly high in tryptophan, and the authors proposed that this acts as a substrate to increase serotonin levels, which may be vulnerable to depletion by chronic stress. At the completion of the studies, all of the participants had higher ratios of plasma Tryp-LNAA (the ratio of plasma tryptophan to the sum of the other large neutral amino acids), believed to be an indirect indication of brain serotonin function.
  
  Recently, de Moura et al. evaluated the effects of whey protein intake on the expression of heat shock protein HSP70 (de Moura. 2013). HSP70 confers cellular tolerance against stressors, and there was a greater increase in the HSP70 expression in the soleus, gastrocnemius, and lungs of the whey protein hydrolysate-fed rats than in the casein-fed rats.

Tsutsumi & Tsutsumi also mention the battle against sarcopenia, where whey is about as useful as it is as a muscle builder in athletes and the support of the gastrointestinal integrity that is mediated by the glutamic acid content of whey which is converted to glutamine and serves as fuel for the intestinal mucosa among the proven health benefits of whey protein, before they conclude their review by stating that we still need studies investigating the mechanisms underlying the effects of whey protein.

Stop protein wheysting!

I have to admit, I am a bit ashamed of how extensively I used the excellent review by Rie and Yasuo M. Tsutsumi when I compiled today's SuppVersity Article. What came out of it, though, is an article with so many facts about the health benefits of whey that I am confident that it contains at least one surprising study result you have not heard of before for each of you... true?

In case it didn't, stay tuned for reports on the future studies investigating the mechanisms underlying the effects of whey protein, Tsutsumi & Tsutsumi demand in the conclusion of their review: I bet you won't have to wait long for the next SuppVersity Whey Protein Article | Comment on Facebook!

References:

• de Moura, Carolina Soares, et al. "Whey protein hydrolysate enhances the exercise-induced heat shock protein (HSP70) response in rats." Food chemistry 136.3 (2013): 1350-1357.
• FitzGerald, Richard J., Brian A. Murray, and Daniel J. Walsh. "Hypotensive peptides from milk proteins." The Journal of Nutrition 134.4 (2004): 980S-988S.
• Hall, W. L., et al. "Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion and appetite." British Journal of Nutrition 89.02 (2003): 239-248. 
• Havea, Palatasa, Harjinder Singh, and Lawrence K. Creamer. "Characterization of heat-induced aggregates of β-lactoglobulin, α-lactalbumin and bovine serum albumin in a whey protein concentrate environment." Journal of Dairy Research 68.03 (2001): 483-497.
• Ikeda, Masanori, et al. "Lactoferrin markedly inhibits hepatitis C virus infection in cultured human hepatocytes." Biochemical and biophysical research communications 245.2 (1998): 549-553. 
• Markus, C. Rob, Berend Olivier, and Edward HF de Haan. "Whey protein rich in α-lactalbumin increases the ratio of plasma tryptophan to the sum of the other large neutral amino acids and improves cognitive performance in stress-vulnerable subjects." The American journal of clinical nutrition 75.6 (2002): 1051-1056.
• Marshall, Keri N. D. "Therapeutic applications of whey protein." Alternative Medicine Review 9.2 (2004): 136-156.
• Pal, Sebely, and Vanessa Ellis. "The chronic effects of whey proteins on blood pressure, vascular function, and inflammatory markers in overweight individuals." Obesity 18.7 (2010a): 1354-1359.
• Pal, Sebely, Vanessa Ellis, and Satvinder Dhaliwal. "Effects of whey protein isolate on body composition, lipids, insulin and glucose in overweight and obese individuals." British journal of nutrition 104.05 (2010b): 716-723.
• Pal, Sebely, Vanessa Ellis, and Suleen Ho. "Acute effects of whey protein isolate on cardiovascular risk factors in overweight, post-menopausal women." Atherosclerosis 212.1 (2010c): 339-344. 
• Pal, Sebely, and Simone Radavelli‐Bagatini. "The effects of whey protein on cardiometabolic risk factors." Obesity Reviews 14.4 (2013): 324-343.
• See D, Mason S, Roshan R. "Increased tumor necrosis factor alpha (TNFalpha) and natural killer cell (NK) function using an integrative approach in late stage cancers." Immunol Invest 21 (2002):137-153.
• Smithers, Geoffrey W. "Whey and whey proteins—from ‘gutter-to-gold’." International Dairy Journal 18.7 (2008): 695-704.
• Tsutsumi, R., and Y. M. Tsutsumi. "Peptides and proteins in whey and their benefits for human health." Austin J Nutri Food Sci 1.1 (2014): 9.
• Watanabe, Akiharu, et al. "Nutritional therapy of chronic hepatitis by whey protein (non-heated)." Journal of medicine 31.5-6 (1999): 283-302.

DHEA Revives Liver of Aged Rats and Improves Antioxidant Reserves and Akt Signaling in Young and Old Rats.

Image 1:  I don't think celebrities realize it, but there is more to anti-aging than an unlined face. New studies show that DHEA could after all help with all sorts of age related diseases (img. antiagingpossible.com)

It's been a while since DHEA was in the news. While I have posted a handfull of mostly beneficial findings related to dehydroepitestosterone (DHEA), the hype that sourrounded its purported anti-aging effect in the late 1990s has completely abated. In view of DHEA's implication  (or rather the lack of the latter) in age-related autoimmune disease, sexual disfunction, osteoporisis, deteroiations of lipid metabolism, type 2 diabetes and cardiovascular and liver disease (Basci. 2007- ignificance of  dehydroepiandrosterone  and  dehydroepiandrosterone  sulfate  in  different  diseases), it is questionable how people beyond the age of 40, when DHEA production declines by 2% per year(!) could not benefit from a carefully planned and monitored DHEA treatment. A group of scientists from Brazil obviously thought the same and decided to take a fresh look at what happens on a molecular level, when 3 (young rats) and 24 months (old rats) old male Wistar-rats are given 10mg/kg deyhdroepitestosterone [human equivalent: 1.62mg/kg; 80kg human: 130mg/day] subcutaneously per day for 5 weeks (Jacob 2011).

Figure 1: Relative changes in total, reduced and oxidized glutathione in young and old rats after 5 weeks on 10mg/kg DHEA (data adapted from Jacob 2011)

As you can see in figure 1, the treatment induced profound increases in total and reduced glutathione and age-dependendly increased (young) or decreased the absolute level of oxidized glutathione (GSSG). Despite the absolute increase in GSSG, usually a marker of oxidative stress, the more important GSH / GSSG ratio, i.e. the ratio of reduced to oxidized glutathion, a more comprehensive marker of the balance of pro- vs. anti-oxidant metabolic processes, improved even more in the twelve young rats, (+6% GSH/GSSG) than in their older companions (+1% GSH/GSSG).

Figure 2: p-Akt levels in young and old rats with and without DHEA supplementation (data adapted from Jacob 2011)

As a faithful student of the SuppVersity, the serine/threonine kinase Akt should not be a stranger to you, after all, mTOR and p706SK (the "muscle builders", you've read about in the context of BCAAs, leucine and exercise-induced protein synthesis), are among its intracellular substrates. In agreement with previous studies, chronic administration of DHEA increased p-Akt-expression in the study at hand (cf. figure 2). The scientists speculate "that the Akt activation in this organ [the liver] is a protective answer" and could, after all, be the underlying reason for the preservation / restauration of hepatic function in the old rats.

Image 2: Oral DHEA supplements are sold for a few bucks over-the-counter (at least in the USA). Yet,
esp. for people under the age of 35, it probably does not make sense to buy and use those. At least, for
as long as it takes for the results of the study at hand to be confirmed in humans. And the allegedly benign 7-Keto DHEA could wreak havoc on your natural corticosteroid metabolism.

So how much DHEA should I take? Given the fact that the name of this blog is SuppVersity, I should have apprehended DeDeRa's question on which form and how much DHEA I would suggest you take. My answer is quite simple: NONE! Why? Well, this is a rodent study done with injectable DHEA. Not only would it be imprudent to extrapolate any dosing suggestions for oral DHEA supplements in humans, without clinical tests, we cannot even be sure that the effects would be identical, even if we hit the right dosage. Thus, while I am convinced that DHEA is probably more benign than many other OTC "supplements", especially people under the age of 30-35 should think twice or better thrice before popping any DHEA supplement - this includes 7-keto, the cortisol-suppressant effects of which can wreak havoc on your natural corticosteroid balance, make you feel tired and sluggish and deprive your body of an important anti-inflammatory pathway.

Most importantly, however, the study does away with the longstanding prejudice that DHEA (at the given dosage) "represent[s] a toxic potential to [the] liver". The isolated finding that endogenous DHEA lead to increased oxidation in the liver (it still does, but the overall pro- vs. anti-oxidant balance still improves!), as well as insufficient funding by the pharmaceutical industry, who obviously is not interested in naturally occuring and thus non-patentable treatment methods, had been one of the primary reasons many scientists decided not to dig deeper into the ameliorative, preventive and restaurative effects of DHEA in the context of age-related diseases. Personally, I hope that the few new studies that have been published, lately, will encourage other researchers to have another look at a hormone with profound yet complex and complicated effects on numerable aspects of the mammalian metabolism.

2g Vitamin C Ameliorate Low Testosterone Levels and Sexual Dysfunction in Diabetic Rats. Usefulness in Normoglycemic Individuals Still Questionable.

Illustration 1: In view of the increase in renal
vitamin C clearance with higher plasma levels
(Friedmann. 1940), it may be sensible to use a
time-released vitamin C formula, or, even
better, eat a serving of veggies or fruits that
are high in vitamin C multiple times a day

Yes, I know, supplemental vitamin C does not ward off the common cold... the same applies for taking super high doses of vitamin C as antioxidant buffers before or around workouts. In fact, studies have shown that the antioxidant overkill of a combination of vitamin C and other powerful antioxidants could negate the beneficial effects exercise has on human blood glucose management. Now, a group of Brazilian scientists has published a rodent study that seems to suggest that in the absence of exercise the addition of 2g (human equivalent for 80kg male) of vitamin C to your diet could partially restore sexually function and increase testosterone levels in diabetic patients (Fernandez. 2011).

In their study, the Fernandez et al. had fed 10 out of 20 hyperglycemic rats vitamin C enriched chow (+150mg) and found that the addition of the water-soluble vitamin had beneficial effects on oxidative strees biomarkers in the erythrocytes, which have proven to be a valuable indicator of stress levels for the whole body (Naziroğlu. 2001; Garg. 2000)] (cf. figure 1),

Figure 1: Stress markers TBARS, SOD, GSHt and GSH/Px in hyperglycemic rats after 30 days on normal (placebo) and vitamin C enriched chow; data expressed relative to normoglycemic controls (data adapted from Fernandez. 2011)

as well as reproductive organ weights, sperm parameters, plasma hormone levels (FSH, LH and testosterone), testicular and epididymal histo-morphometry and histopathology.of the hyperglycemic rats (cf. figure 2).

Figure 2: Organ weights (*visceral fat / 100g), reproductive hormones and sperm number and quality in hyperglycemic rats after 30 days on normal (placebo) or vitamin C enriched chow; values expressed relative to normoglycemic control (data adapted from Fernandez. 2011)

Vitamin C supplemented or not, compared to the normoglycemic control,  the diabetic rats must still be regarded as partially impotent and overall sickly, which is an observation the scientists omit, when they conclude

[...] the present study showed that vitamin C supplementation minimized some alterations in the male reproductive system caused by hyperglycemia such as reduction of testosterone and LH levels and impairment in sperm morphology. [italicization by Dr. Andro]

After all, what's the worth of a "minimizing" the negative effect on testosterone levels to  -71%? This may be 10% less damage than without vitamin C, but wouldn't it be much better not to get yourself into such a misery in the first place?

Note! Not everything that is good for sick people makes a viable addition to the supplementation regimen of a healthy or even athletic person. Even Fernandes and her co-workers emphasize that "is possible that the beneficial effects of vitamin C supplementation are only relevant to those individuals with low levels of vitamin C and high levels of oxidative stress that occur in hyperglycemic condition."

Well, regular exercise and the avoidance of high fructose corn syrup and the other sweet suspects you poise yourself with on a daily basis would be the way to go - and you know that!

Rodent Study Suggests: Selenium, Nature's Neuronal Corrosion Inhibitor Could Protect the Brains of Hard Training Athletes from Oxidative Damage.

Image 1: Selenium is a naturally occurring mineral
involved in a host of metabolic processes.

Are you a hard training athlete? A weekend warrior? Marathon runner? Or just an an average fitness-enthusiast? Yes? Did you ever think about what an exhausting workout, let alone arduous marathon running may do to your brain? No? Then it may come as a surprise to you that other than regular moderate physical exercise, which has repeatedly been shown to exert beneficial effects on mental and physical development, intense exercise precipitates oxidative stress not only in the working muscle groups, but within your whole body - including your brain, where the exercise-induced increase in free-radicals may dramatically increase lipid oxidation (Goldfarb.1996; Kanter. 1998).

Based on observations with other antioxidants and the well-established involvement of selenium in the activation of the master-antioxidant glutathion, researchers from the Selcuk University in Konya, Turkey, hypothesized that supplementation with yet to be determined amounts of selenium might ameliorate the detrimental effects of arduous exercise (Akil. 2011). To verify their hypothesis, the Akil et al. subjected a group of 4-6 month old Sprague-Dawley rats to one out of four treatments for 4 weeks:

• group 1: unsupplemented sedentary control
• group 2: selenium supplemented, sedentary control
• group 3: swimming control (30 minutes in a closed glass-swimming pool; 50x50cm)
• group 4: selenium supplemented + swimming (same as group 3)

Both, the animals in group 2 and group 4 were supplemented with additional  0.6mg/kg of selenium selenite per day. For an 80kg adult human being the human equivalent dose of 0.098mg or 90mcg per kilogram of body weight would amount to 7.8mg of additional selenium per day, a dose, of which textbook knowledge tells us that it is way beyond the upper-limit of 0.8mg/day. Yet, for the rats, this supposedly toxic amount of selenium turned out to be quite beneficial.

For more on the beneficial effects high doses of selenium may have and a short discussion of toxicity issues, see my previous post on "NAC + Zinc + Selen = Silver Bullett Against Mercury Poisoning"

As the data in figure 1 shows, the non-supplemented arduously exercising rats (group 3) had by far the highest malondialdehyde (MDA is an accepted marker of unwanted oxidation) levels. On the other hand, the MDA levels of the supplemented group were reduced by 11%. Compared to the sedentary controls, which had identical (i.e. within the statistical margin) MDA levels, the malondialdehyde content of their brains was still elevated by 57%. While selenium supplementation may thus have ameliorated the increase in brain MDA levels, it was not able to completely protect the rat-brains from free-radical induced oxidation processes.

Figure 1: Malondealdehyde (MDA) and glutathione levels in rat brains after 30 minutes of exhaustive swimming exercise (data adapted from Akil. 2011)

Interestingly, in both, the supplemented, as well as the non-supplemented exercise groups brain glutathion levels (GSH) increased by 124% and 71%, respectively - probably to protect the brain from extensive oxidation. Under this assumption the selenium induced increase in glutathione levels, which lead to a 53% greater GSH increase in the brains of the rats in the selenium supplemented swimming group, would adequately explain the lower MDA levels of the high selenium group.

While it would have been nice to see a comparison of the effects of different doses and exercise protocols, the study at hand is just another hint a the importance of a mineral, that was believed to be toxic up to the late 1950. Consequently, this is neither the first, nor will it be the last time you read about this extraordinary mineral on the SuppVersity - stay tuned for more!

Iodine Induced Reduction in Hepatic Deiodinase Activity Leads to Hypothyrodism and the Accumulation of Liver Fat That May Eventually Pave the Way to Diabesity

While us Westerners think of goitre mostly as a result of iodine deficiency, the Chinese have learned by hard that the opposite is about as likely - goitre in response to iodine in the drinking water is a huge health problem in certain parts of the country (Zheng. 2000)

As colorful as the web may have become, it is still full of paradigmatic black-and-white thinking: The world is either black or white and if you browse the blogosphere, it would appear that iodine would certainly belong to the white part of our world. That in exactly those people who are often referred to as an example of the multitude of beneficial health effects, namely the Japanese, a high intake of iodine has repeatedly been shown to be associated with low thyroid function and even full-blown hypothyroidism, on the other hand, is something you will probably not learn from the tons of unreferenced stuff you'll find on the Internet about how good, if not essential it was for your health to take copious amounts of iodine everyday (about the same amount you would take if the nuclear powerplant next to you exploded to saturate and shut down your thyroid and prevent it from taking up the radioactive iodine).

The Ying and Yang of high and low iodine intake

A recently published rodent study from the Huazhong University of Science and Technology, the Binzhou Medical University and the Shen Zhen Center for Chronic Disease Control, in China (Xia. 2013) does now shed some light onto the underlying mechanisms of the well-known thyroid disrupting effects of the structural backbone of all mammalian thyroid hormones, iodine. While the whole spectrum of disorders of iodine excess includes hypothyroidism, hyperthyroidism, autoimmune thyroiditis,embryo toxicity, and depression of brain development (Guo. 2006; Rose. 2001; Roti. 2001; Yang. 2006) Yun Xia et al. are probably the first to investigate its hazardous effects of iodine excess on the liver.

To this end, the Chinese researchers supplemented rats on a standard diet containing a baseline level of 365μg/kg iodine with different doses of iodine in the form of potassium iodate (KIO3) in the drinking water for 3 months:

"In 2000, the Chinese Nutrition Society stated that the recommended nutrient intake (RNI) of iodine of adults is 150μg/day and the tolerable upper intake level (UL) is 1,000μg/day.
Conversely, intake of iodine at about sixfold of its RNI may induce injury. In addition, many excess iodine animal experimental data indicate that ten times the normal iodine intake in mice for about 3 months can cause damage. Moreover,the results of our previous experiment show that drinking 1.2 mg I/L iodine water for 1 month had no significant effect on serum lipid metabolism, while prolonged exposure for 3 months induced an increase of serum cholesterol." (Xia. 2013)

According to these results, the mice in the study were randomized to receiver either 0, 0.3, 0.6, 1.2, 2.4, and 4.8 mg I/L iodine, corresponding to 0-, 1-, 2-, 4-, 8-, and 16-fold of the adequate/normal iodine intake for 3 months to explore the dose-dependent effect of iodine on hepatic steatosis. In the course of the trial, dood consumption, water consumption of each group, were recorded meticulously and the weight gain of each mouse was recorded daily.

Additionally, another 60 weaning female Balb/c mice were randomly assigned to six groups and given iodine at different levels (0, 0.3, 0.6, 1.2, 2.4, and 4.8 mg I/ml) for 1 month just for
measuring the oxidative stress parameters in serum and liver.

Figure 1: Triglyceride content in liver and serum, as well as SREBP-1c and fatty acid syntethase (FAS) activity after 3 months on diets with additional iodine (Xia. 2013)

While neither food intake, nor water consumption or weight gain differed significantly between the groups (data not shown), a brief glance at the data in figure 1 should suffice to see that there was a dose-dependent increase in hepatic triglyceride levels (=fatty liver disease) that was accompanied by corresponding increases in serum triglyceride, when the liver was clogged up to the max - as it appears to be the case with 8x or 16x higher than normal levels in the diet (for humans that would thus be ~1.6g or 3.2g of potassium iodiate).

Figure 2: Total antioxidant capacity, glutathione peroxidase, SOD, and lipid peroxidation (MDA) after 1 and 3 months expressed relative to untreated control (Xia. 2013)

The fatty acid accumulation in the liver was accompanied by profound changes in total antioxidant and SOD and glutathione status, as well as significant increases in lipid oxidation (as indicated by the +61% and +85% increase in MDA in the groups with the highest intake of supplemental iodine). Contrary to the commonly propagated myth that tons of supplemental iodine would increase the thyroid function these changes were accompanied by profound decreases in D1 deiodinase activity and correspondingly decreased conversion of T4 to T3 (see figure 3).

Figure 3: Changes in thyroid hormone and deiodinase levels; expressed. rel. to control (Xia. 2013)

It should thus not surprise you, that the levels of TSH and T4 in the rodents increased, while those of T3 decreased (no conversion = hypothyroism, no matter how much T4 you got floating around).

Low D1 => Low T3 => fatty liver disease

In fact, the reduced local conversion of T4 to T3, is also behind the accumulation of triglycerides in the liver and blood of the animals, as the

"[r]educed plasma T3 level resulted in the upregulation of SREBP-1c mRNA and FAS mRNA that ultimately led to the accumulation of triglycerides in the liver. [...] Evident hepatic steatosis was observed in mice challenged with 2.4 and 4.8 mg I/L iodine in drinking water. " (Xia. 2013)

As a SuppVersity student you know about the downstream effects, but I guess it makes sense to reiterate them for the newbies: Since the liver plays a, if not the pivotal role in systemic lipid homeostasis the reduced oxidation of triglycerides and the increased storage will sooner or later lead to an increased secretion of triglyceride-rich lipoprotein (VLDL) as a compensatory response by which the liver will desperately try to spread the lipid burdon to other organs and tissues. Overwhelmed with the sudden onslaught of triglyceride laden VLDL particles which are easily oxidized during their voyage through your blood stream, this opens the door to a narrowing of the arteries, cardiovascular disease and stroke.

---

For the majority of you, overtraining and undereating is probably a much greater threat, when it comes to hypothyrodism (learn more about "self-inflicted hypothyrodism"). However, contrary to excess iodine intake that will not clog up your liver and arteries and eventually cause heart disease and stroke.

Bottom line: If we assume based on the available epidemiological data that the general mechanism was identical in human beings, the ingestion of large amounts of iodine which are often touted as a remedy to all sorts of metabolic syndroms may in fact exert the exact opposite effects.

Yet, although I would be cautious about extrapolating the exact cut-off levels, it appears that dietary intakes in the 800µg range and thus 4-6x more than the RDA can still be considered relatively save. So if you are neither taking high dose supplements or living on tons of seaweed, this is probably not much of a concern for most of you. In addition it would warrant investigation if / to which extent the addition of extra selenium would ameliorate these effects. After all, the latter has been shown to have protective effects against iodine intoxication in the very same rodent model in a 2006 study by Xu et al. (Xu. 2006).

References:

• Guo H, Yang X et al. Effect of selenium on thyroid hormone metabolism in filial cerebrum of mice with excessive iodine exposure. Biol Trace Elem Res. 2006; 113:281–295. 
• Rose NR, Bonita R et al. Iodine: an environmental trigger of thyroiditis. Autoimmun Rev. 2002;  1:97–103.
• Roti E, Uberti ED. Iodine excess and hyperthyroidism. Thyroid. 2001;11:493–500.
• Xia Y, Qu W, Zhao LN, Han H, Yang XF, Sun XF, Hao LP, Xu J. Iodine Excess Induces Hepatic Steatosis Through Disturbance of Thyroid Hormone Metabolism Involving Oxidative Stress in BaLB/c Mice. Biol Trace Elem Res. 2013 May 28. 
• Xu, J, Yang, XF., Guo, HL, Hou, XH Liu, LG, & Sun, XF. Selenium supplement alleviated the toxic effects of excessive iodine in mice. Biological trace element research; 2006 111(1-3), 229-238. 
• Yang XF, Xu J et al. Developmental toxic effects of chronic exposure to high doses of iodine in the mouse. Reprod Toxicol. 2006: 22:725–730. 
• Zhao J, Wang P, Shang L, Sullivan KM, van der Haar F, Maberly G. Endemic goiter associated with high iodine intake. Am J Public Health. 2000 Oct;90(10):1633-5.